A mechanism is suggested for the regulation of the immune response that involves antigen-binding and anti-idiotypic lymphocytes. The cross-linking of receptors is postulated to be a general mechanism for triggering T cells, B cells and cytotoxic effector cells (e.g. macrophages). A key role in regulation is ascribed to antigen-specific T cell-dependent factors, which are assumed to be able to block the receptors of both T cells and B cells of the anti-idiotypic specificities. The simple postulates of the model lead to feasible mechanisms for the helper, suppressor and killer roles of T cells, cellular and humoral immune responses, low zone tolerance and the tolerogenic effects of monomers, immune memory, antigenic competition, the abrogation of tolerance with cross-reacting antigens, the usefulness of the switch from IgM to IgG, and self-tolerance to both serum antigens and cell surface antigens. Biological roles are suggested for one of the Ia antigens and beta 2-microglobulin. The theory leads to a number of predictions, which can be tested experimentally. A simple mathematical model is included, which provides an indication of how the theory may be further developed on a quantitative basis.
Alloimmune mice (mice that have been exposed to cells from another murine strain) were shown to make antibodies against gp120 and p24 of human immunodeficiency virus (HIV), and mice of the autoimmune strains MRL-lpr/lpr and MRL-(+)/+ made antibodies against gp120. This is surprising because the mice were not exposed to HIV. Furthermore, anti-anti-MHC antibodies (molecules that have shapes similar to those of major histocompatibility complex molecules) were detected in both alloimmune sera and MRL mice. These results are discussed in the context of a possible role for allogeneic stimuli in the pathogenesis of acquired immunodeficiency syndrome, as suggested by an idiotypic network model.
Considerations from a network theory of the immune system suggest that human immunodeficiency virus and allogeneic stimuli may act synergistically to cause AIDS. The immune responses to these stimuli include two components that are directed against each other. In some AIDS risk groups other antigens that mimic major histocompatibility complex antigens may substitute for allogeneic stimuli. Implications for the prevention of AIDS are discussed.The idea that human immunodeficiency virus (HIV) is the sole cause of AIDS (without any cofactors) and is directly responsible for the depletion of CD4-bearing T cells is currently being questioned by many researchers for several reasons. A surprisingly low number of T cells are infected with HIV in AIDS (1), and immunosuppression occurs prior to depletion of CD4 cells (2). Furthermore, immunity against HIV does not protect against AIDS; AIDS patients have high quantities of anti-HIV antibodies in their sera (3) and generate a strong anti-HIV cytotoxic T-cell response (4) but are not protected. In fact, people tend to become seriously ill only after they make anti-HIV antibodies. In spite of intensive research, a detailed mechanism explaining T-cell depletion in vivo, only on the basis of HIV infection, has not been characterized.An alternative possibility being considered by several groups of researchers is that HIV induces a deleterious immune response that attacks the immune system itself (5-15). In this paper, we describe an immunological process that could lead to AIDS. Network RegulationThe recognition of variable (V) regions by lymphocytes and vice versa is widely believed to be a central aspect of the specific regulation of the immune system (16). The relative levels ofpopulations oflymphocytes and the topology oftheir interactions are then key aspects of a description of the system. Some lymphocyte populations recognize an invading antigen, and some have V regions that functionally resemble the antigen in that they have complementarity to the V regions of antigen-specific clones. Specific interactions between these populations are believed to regulate the immune response. An explicit network model accounts for a considerable range of phenomena, including memory, separate roles for IgM and IgG, helper T cells, suppressor T cells, and specific T-cell factors (10,11,(17)(18)(19)(20)(21).The theory we describe here emerges from that model. An important component of the theory is the concept of network focusing, which refers to the ability of the network to select clones that are images of particular antigens, including self antigens. A second component is the idea that there is a major axis of specificities in the immune system, bounded by self class I and class II major histocompatibility complex (MHC) antigens. We suggest AIDS is a consequence of a destabilization of the system after excessive stimulation along its major axis.T (Fig. 1). Each suppressor T cell is idiotypically connected to a large number of helper T cells and the suppressor T cells are said ...
BackgroundThe symmetrical immune network theory, developed in 1975, is based on the existence of specific T cell factors and hypothesizes that normal IgG immune responses comprise the production of 2 kinds of antibodies, namely antigen-specific antibodies and anti-idiotypic antibodies.ObjectiveThe aim of this study was to confirm the existence of specific T cells factors and to show that immunization of C3H mice with BL/6 skin or using nominal antigen for immunization (Tetanus Toxoid) induced production of antigen-specific (anti-BL/6 or antitetanus) antibodies plus anti-idiotypic antibodies (C3H anti-anti-C3H). Subsequently, we investigated the role of combinations of antigen-specific and anti-idiotype antibodies in a variety of animal models of clinical diseases.MethodsAntigen-specific antibodies were produced by conventional immunization of mice (eg, with tetanus toxoid or by skin allografting). Subsequent anti-idiotypic antibodies were derived by exhaustive absorption of antigen-specific antibody, with confirmation of anti-idiotypic specificity by binding to relevant target antigen-specific antibodies in an enzyme-linked immunosorbent assay (ELISA). Antigen-specific plus anti-idiotypic antibodies were then used to modulate skin allograft survival, dextran sulfate sodium (DSS)-induced colitis, ovalbumin (OVA)-induced IgE production, and breast cancer growth in mice.ResultsInfusions of anti-BL/6 antibodies together with BL/6 anti-anti-BL/6 antibodies specifically suppressed (>85%) an immune response to BL/6 lymphocytes in C3H mice. The two kinds of antibodies with complementary specificity are hypothesized to stimulate 2 populations of T lymphocytes. Coselection of these 2 populations leads to a new stable steady state of the system with diminished reactivity to BL/6 tissue. A combination of anti-C3H and C3H anti‑anti-C3H IgG antibodies down-regulated inflammation in a mouse model of inflammatory bowel disease (>75%) and attenuated anti-IgE production and sensitization to produce IL4 cytokines (>70%) in an OVA-allergy model. Combination of C3H anti‑BL/6 and BL/6 anti-anti-BL/6 antibodies decreased tumor growth and metastases (>705) in an EMT6 transplantable breast cancer model.ConclusionsUse of a combination of antigen-specific and anti-idiotypic antibodies has potential as a new class of vaccines.
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